Plasma drug level oscillations are commonly associated with multiple dosing of conventional dosage forms. For example, conventional dosage forms often exhibit a deleterious burst phenomenon where most or nearly all of the drug is released into the plasma in a relatively short period of time. One aspect of research on controlled or sustained-release delivery systems involves designing a system that has the potential to produce steady-state plasma drug levels. Ideally, drug level oscillations should be minimized and more constant plasma drug levels over time should be achieved by the use of controlled or sustained-release formulations.
With many drugs, the basic goal of therapy is to provide a delivery system that is capable of providing steady-state plasma or tissue drug levels that are considered therapeutically effective and to maintain these levels without encountering any safety concerns. A basic objective is to optimize the delivery of drugs to maintain a level of efficacy in spite of fluctuations that may take place in the environment where the drugs are released. Therefore, a controlled or sustained-release formulation should be capable of providing a therapeutically effective level of drug, which allows a practitioner to target the therapeutic window of efficacy of the drug, while controlling the plasma drug levels without the deleterious burst phenomenon commonly associated with conventional drug forms. In certain pharmacological applications where high initial concentration of drug is needed, burst release profile could also be desired.
Additionally, practioners can achieve desirable therapeutic advantages by the use of controlled or sustained-release formulations that are able to minimize the frequency of dosing that is sometimes required for a variety of dosage forms. This allows one to improve patient compliance and make the product more convenient.
“Controlled or sustained-release” as used herein refers to the release of a bioactive compound from a medical device surface at a predetermined rate. Controlled or sustained release implies that the bioactive compound does not come off the medical device surface sporadically in an unpredictable fashion and does not “burst” off of the device upon contact with a biological environment. However, the controlled or sustained-release formulation of the present invention does not preclude a formulation exhibiting a “burst” phenomenon. The controlled or sustained release may be steady state (commonly referred to as “timed release” or zero-order drug release kinetics) such that the drug is released in even amounts over a predetermined time (with or without an initial burst phase), or may be a gradient release.
Controlled or sustained-release formulations are designed to achieve a prolonged therapeutic effect by continuously releasing a medication over an extended period of time after administration of a single dose. A preferred profile in some cases, in controlled or sustained release is zero-order drug release kinetics. Zero-order drug release kinetics can be assessed in in-vitro dissolution models that mimic the stomach or parenteral environment by showing constant release of a drug over a specified period of time.
There are a number of technologies currently available that have been used to provide zero-order drug release kinetics with certain therapeutic agents, such as analgesic and anesthetic drugs (e.g. lidocaine, fentanyl, sufentanil, codeine, hydromorphone, bupivacaine, and trifusal) as well as larger molecules such as cyclodextrin. These include osmotic-based approaches, liposomal systems and bioerodible polymers. Additionally, numerous design concepts have been attempted, and various transport mechanisms including diffusion/dissolution, chemical reactions, osmosis, erosion, and swelling have been explored in connection with identifying delivery systems that exhibit zero-order drug release kinetics. One of the concepts that has demonstrated zero-order drug release kinetics is from hydrophilic swellable matrices with various geometries in connection with morphine, indomethacin and diltiazem HCl, as set forth by Yukinari, et. al, 1993, in “Swelling controlled zero-order and sigmoidal drug release from thermo-responsive poly(N-isopropylacrylamide-co-butyl methacrylate)hydrogel” and by Okano, et. al, in 1990, in “Thermally on-off switching polymers for drug permeation and release”. Drug diffusion from the matrix is accomplished by swelling, dissolution and/or erosion. The major component of these controlled-release systems is a hydrophilic polymer. In general, diffusivity is high in polymers containing amorphous flexible chains and low in crystalline polymers. With changes in morphological characteristics, the mobility of the polymer segments changes and diffusivity can be controlled. Addition of other components, such as a drug, another polymer, soluble or insoluble fillers, or a solvent, can alter the intermolecular forces, free volume, glass transition temperature, and consequently, can alter the transport mechanisms.
U.S. Pat. Nos. 3,997,512, 4,048,256, 4,076,798, 4,095,600, 4,118,470, and 4,122,129, assigned to American Cyanamid Company, describe biocompatible and absorbable polycondensation polyesters, which are the polycondensation product of diglycolic acid and glycols such as ethylene glycol, diethylene glycol, 1,2-propylene glycol, 1,3-propylene glycol, and the like. Specifically, U.S. Pat. No. 4,095,600 describes a reaction product of (a) about 2 to 50% by weight of the polycondensation polyester and (b) polyglycolic acid, based on the total weight of the polycondensation polyester and polyglycolic acid, to form a self-supporting polymeric film for use, for example, in drug delivery. However, these references are silent with respect to the zero-order drug release kinetics exhibited when the polycondensation polyesters are used in combination with a drug.
There also remains a need to have controlled or sustained-release formulations for certain drugs, where zero-order drug release kinetics is desirable.